The biological timing system is located in the nervous system of a wide variety of animals and consists of an entrainable clock which generates circadian information, which then governs the rhythmic behavior. Alterations of this system profoundly affect the animal's (including human) performance and are closely associated with certain types of affective disorders. Since the signal flow (input to pacemaker to output) for the circadian rhythms is common to most animal species, basic information obtained from research in the fruit fly is intertwined with clinical significance in higher animals. Most molecular genetic studies of the biological timing system in Drosophila have focused on the clock genes period and timeless. In this proposal, consideration is given to neuroendocrine factors that may also affect the fly's pacemaking system. A neuropeptide called pigment-dispersing hormone (PDH) has been known to be involved in the circadian rhythmic changes on integumental color in crustaceans. Similar neuropeptides have been identified, and their biological functions appear related to insect circadian rhythms. Recently, cDNA of the Drosophila PDH homolog (Dm-PDF) has been cloned by the applicant, and the proposed research will extend this initial accomplishment to define the roles of Dm-PDF in the regulation of the fly's biological timing system using comprehensive molecular genetic approaches along with behavioral analyses.